Molecular Titration and Ultrasensitivity in Regulatory Networks

Buchler, Nicolas E.; Louis, Matthieu

doi:10.1016/j.jmb.2008.09.079

Cited by 250 publications

(341 citation statements)

References 74 publications

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“…3C). Of note, similar phenomena have been reported in very different systems where the strong interaction between two chemical entities (33,34) such as mRNA-sRNA (35,36) or protein-protein (37) has been shown to result in ultrasensitivity, namely to a very sharp dependence in the level of one chemical entity on the production rate of the other. As in previous analyses of ultrasensitive processes, the key factor for the amplification of noise is the strong binding of the two entities (Fig.…”

Section: Resultssupporting

confidence: 73%

Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence

Rotem

Loinger²,

Ronin³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

322

299

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In the face of antibiotics, bacterial populations avoid extinction by harboring a subpopulation of dormant cells that are largely drug insensitive. This phenomenon, termed "persistence," is a major obstacle for the treatment of a number of infectious diseases. The mechanism that generates both actively growing as well as dormant cells within a genetically identical population is unknown. We present a detailed study of the toxin-antitoxin module implicated in antibiotic persistence of Escherichia coli. We find that bacterial cells become dormant if the toxin level is higher than a threshold, and that the amount by which the threshold is exceeded determines the duration of dormancy. Fluctuations in toxin levels above and below the threshold result in coexistence of dormant and growing cells. We conclude that toxin-antitoxin modules in general represent a mixed network motif that can serve to produce a subpopulation of dormant cells and to supply a mechanism for regulating the frequency and duration of growth arrest. Toxinantitoxin modules thus provide a natural molecular design for implementing a bet-hedging strategy.single-cell | stochasticity | systems biology

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Section: Resultssupporting

confidence: 73%

Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence

Rotem

Loinger²,

Ronin³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

322

299

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“…Gal1p and Gal3p competitively sequester a common protein, Gal80p. Competitive binding interactions and molecular sequestration can produce ultrasensitivity, which is a crucial building block for a bistable system (31)(32)(33)(34). Therefore, we suspected that the competitive sequestration of Gal80p by Gal1p and Gal3p may constitute a critical feature of the system.…”

Section: Properties Of Positive Feedback Loops Established By Molecularmentioning

confidence: 99%

Synergistic dual positive feedback loops established by molecular sequestration generate robust bimodal response

Venturelli

El-Samad

Murray

2012

Proc. Natl. Acad. Sci. U.S.A.

120

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Feedback loops are ubiquitous features of biological networks and can produce significant phenotypic heterogeneity, including a bimodal distribution of gene expression across an isogenic cell population. In this work, a combination of experiments and computational modeling was used to explore the roles of multiple feedback loops in the bimodal, switch-like response of the Saccharomyces cerevisiae galactose regulatory network. Here, we show that bistability underlies the observed bimodality, as opposed to stochastic effects, and that two unique positive feedback loops established by Gal1p and Gal3p, which both regulate network activity by molecular sequestration of Gal80p, induce this bimodality. Indeed, systematically scanning through different single and multiple feedback loop knockouts, we demonstrate that there is always a concentration regime that preserves the system's bimodality, except for the double deletion of GAL1 and the GAL3 feedback loop, which exhibits a graded response for all conditions tested. The constitutive production rates of Gal1p and Gal3p operate as bifurcation parameters because variations in these rates can also abolish the system's bimodal response. Our model indicates that this second loss of bistability ensues from the inactivation of the remaining feedback loop by the overexpressed regulatory component. More broadly, we show that the sequestration binding affinity is a critical parameter that can tune the range of conditions for bistability in a circuit with positive feedback established by molecular sequestration. In this system, two positive feedback loops can significantly enhance the region of bistability and the dynamic response time.gene-regulatory network | phenotypic variation | ultrasensitivity

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“…Assuming rapid binding between repressors and activators, the fraction of activators that are not sequestered by the repressors and that are thus transcriptionally active is described by following protein-sequestration function (Fig. 1d) [59,[70][71][72]:…”

Section: Introductionmentioning

confidence: 99%

Protein sequestration versus Hill‐type repression in circadian clock models

Kim¹

2016

IET syst. biol.

107

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Circadian (~24hr) clocks are self-sustained endogenous oscillators with which organisms keep track of daily and seasonal time. Circadian clocks frequently rely on interlocked transcriptionaltranslational feedback loops to generate rhythms that are robust against intrinsic and extrinsic perturbations. To investigate the dynamics and mechanisms of the intracellular feedback loops in circadian clocks, a number of mathematical models have been developed. The majority of the models use Hill functions to describe transcriptional repression in a way that is similar to the Goodwin model. Recently, a new class of models with protein sequestration-based repression has been introduced. Here, we discuss how this new class of models differs dramatically from those based on Hill-type repression in several fundamental aspects: conditions for rhythm generation, robust network designs and the periods of coupled oscillators. Consistently, these fundamental properties of circadian clocks also differ among Neurospora, Drosophila, and mammals depending on their key transcriptional repression mechanisms (Hill-type repression or protein sequestration). Based on both theoretical and experimental studies, this review highlights the importance of careful modeling of transcriptional repression mechanisms in molecular circadian clocks.

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Molecular Titration and Ultrasensitivity in Regulatory Networks

Cited by 250 publications

References 74 publications

Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence

Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence

Synergistic dual positive feedback loops established by molecular sequestration generate robust bimodal response

Protein sequestration versus Hill‐type repression in circadian clock models

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